Fluorochemicals, and especially perfluorochemicals, are known to be chemically and pharmaceutically inert and to be capable of dissolving and transporting large amounts of oxygen. Because of these properties, fluorochemical emulsions have been proposed as intravenously acceptable oxygen transport agents, and as "artificial blood" or "red blood cell substitutes" for human and animal patients. Fluorochemical emulsions thus have potential application in for example, emergency treatment, elective, emergency and trauma surgery, myocardial infarct treatment, coronary balloon angioplasty, stroke treatment, intraperitoneal oxygenation, and surgery involving hemodilution. Fluorochemical emulsions also have potential use as contrast agents for various imaging modalities such as nuclear magnetic resonance, ultrasound and x-ray. See European Patent Publication 231 091 and PCT publication W089/10118. In addition, fluorochemical emulsions have been proposed as vehicles for supplying oxygen to the lungs in the field of liquid breathing. Fluorochemical emulsions thus have potential application in for example, the treatment of respiratory distress syndrome, cystic fibrosis, ventilator distress, pneumonia, edema and other pulmonary complications. In liquid breathing applications, fluorochemical is also transported to the bloodstream.
If not artificially removed from the patient's blood, fluorochemicals are cleared into the cells of the reticuloendothelial system (RES) over two to six day period, depending upon the dosage. See, e.g., K. Yokoyma et al., "Preparation of Perfluorodecalin Emulsion, An Approach to the Red Cells Substitute," Fed. Proc., (34), pp. 1478-83 (1975). However, natural elimination, via the RES, may result in retention of some of the fluorochemical in the patient's organs. See J. Lutz, "Effect of Perfluorochemicals on Host Defense, Especially on the Reticuloendothelial System," Int'l Anesthesiology Clinics, (23), 63-93 (1985). Therefore, development of an extracorporeal method for removal of fluorochemical from blood is desired as an improved alternative to natural excretion.
One approach to separation of fluorochemical from whole blood is referred to in T. Agishi et al., "Retrieval of Artificial Blood Cells (Perfluorochemical) from Whole Blood," Trans. Am. Soc. Artif. Organs, (20), pp. 456-59 (1983). Agishi refers to the attempted separation of a fluorochemical emulsion from the whole blood of dogs by batch centrifugation with a Haemonetics V-50 apheresis device (manufactured by Haemonetics Corporation, Braintree, Mass.). Agishi states that the Haemonetics V-50 centrifugation bowl accumulated trapped fluorochemical which was very difficult to remove. This difficulty arose even though the greatest volume of fluorochemical-containing blood processed was only 2.5 liters at a very low initial hematocrit of 4% and a low initial fluorocrit of 8% (cc of fluorochemical per 100 ml of blood). Agishi does not suggest a clinically practical method of separating fluorochemical from whole blood using batch centrifugal apheresis with the Haemonetics V-50. Another attempt at using the Haemonetics V-50 in the separation of fluorochemical emulsion from blood is referred to in T. Agishi et "(Pyridoxalated Hemoglobin)--(Polyoxethylene) Conjugate Solution As Blood Substitute For normothermic Whole Body Rinse-Out," Biomat., Art. Cells. Art Org., 16(1-3), 261-270 (1988). There, an attempt was made to reduce the level of pathogenic substances (e.g. digoxin) in the blood of dogs by replacing approximately 2,000 to 2,500 ml of blood with the fluorochemical emulsion Fluosol-DA. Agishi reported that batch centrifugation using the Haemonetics V-50 removed only 60 to 70% of the fluorochemical from the dogs, leaving a residual amount stated to be beyond the recommended maximum. Again, there was no suggestion of a clinically practical method of separating fluorochemical from whole blood. The Haemonetics V-50 centrifugal apheresis device performs batch separation on discrete quantities of blood. Batch centrifugal apheresis devices, such as the Haemonetics V-50, operate in a cycle in the following manner. The first part of the cycle, called the "draw cycle", draws blood into a spinning centrifuge bowl where the components are separated by centrifugal force. Heavier fractions are spun to the outer wall of the centrifuge, while lighter fractions move to the center. When used to separate fluorochemical from whole blood, the Haemonetics V-50 spins the heaviest component, the fluorochemical-enriched fraction, to the outer wall of the centrifuge and the lighter component, the whole blood-enriched fraction to the center of the centrifuge. Once the bowl is full of fluid, continued pumping of the blood fluorochemical mixture displaces the whole blood enriched fraction through the exit port. The next part of the cycle, called the "return cycle", occurs when the centrifuge bowl is full of the fluorochemical-enriched fraction. During the return cycle, the remaining heavier components in the bowl must be drawn off to make way for the next batch. Unfortunately, separated fluorochemical cannot be removed from the centrifuge system as it is too viscous to be drawn off and therefore remains in the centrifuge bowl for the duration of processing. Eventually the fluorochemical-enriched fraction completely fills the centrifuge bowl preventing flow into the bowl, and thus further processing. Therefore, the amount of fluorochemical that can be separated from whole blood by the Haemonetics V-50, or any batch processing device, is inherently limited by the volume of the centrifuge bowl. The Haemonetics V-50 centrifuge can be outfitted with bowls having volumes of 125, 225 or 350 ml.
Another centrifugal apheresis device, the Fenwal CS-3000 Plus (Baxter Healthcare Corporation, Deerfield, Ill.), equipped with a centrifuge belt, is similarly limited by its centrifuge belt volume of about 250 ml. Although the CS-3000 is not a batch processor, upon experimentation it has been shown by the inventors of the invention described hereinafter to share with the Haemonetics V-50 the same characteristic of production of an excessively high viscosity fluorochemical fraction. The fluorochemical fraction essentially clogged flow through the apparatus and the CS-3000 also failed. Because the separation methods characterized by the Haemonetics V-50 and the Fenwal CS-3000 Plus generally result in fluorochemical clogging the apparatus, they fail to achieve clinically useful separation of fluorochemical from whole blood, which generally requires that all of a patient's blood be processed.
In addition to fluorochemical clogging of the centrifuge bowl, the above centrifugal apheresis devices often require relatively large operating volumes, above 250 ml. This also limits their utility in applications for the separation of fluorochemicals from whole blood. At first glance, a larger operating volume may appear to be a solution to the fluorochemical clogging problem since more fluorochemical could be separated before flow into the centrifuge stopped. In practice, however, taking significant blood volumes from patients can cause them to become hypotensive. Furthermore, most emergency and trauma patients, and many surgical patients, are already hypotensive, and taking a large extracorporeal volume from them for centrifugation is contraindicated.
In brief summary, the possibility of expanding the applications of fluorochemicals in medicine by using a fluorochemical blood substitute for a short time and then extracorporeally removing it from a patient's blood has not been achieved by the use of known centrifugal apheresis devices or any other methods.